1. FIELD OF THE INVENTION
The present invention is directed to novel pro-drug forms of digoxin and namely, the mono- through penta- ester derivatives thereof formed by the reaction of digoxin with a naturally occurring or synthetic amino acid.
As employed in this application, the term "pro-drug" denotes an art recognized expression, indicating that a derivative of a proven and known drug has been prepared, which after administration in suitable dosage form, will "cleave" in the body, thus releasing the basic drug. The higher solubility and/or better absorption characteristics of the pro-drug in conjunction with protecting, in the pro-drug, the active sites of the molecule against undesired metabolic pathways will permit such drug to obtain a higher and more reproducible bioavailability level than that which could be obtained if the basic drug per se were administered. Thus, in the instant application, the derivatives described above will permit digoxin to attain a superior bioavailability level in the bloodstream, than that which could be obtained if digoxin were administered per se.
2. DESCRIPTION OF THE PRIOR ART
Digoxin is a cardiotonic drug, used in the field of medicine to achieve an increase in the force of myocardial contraction. Basically, digoxin is a conduction system depressant which acts in such a manner as to decrease cardiac rate.
The structural formula for digoxin is set out below, and conventionally speaking, the dose administered to a patient (orally) to achieve digitalization is approximately 1.5 mg and thereafter, a maintenance dose of approximately 0.5 mg is required. ##STR3##
Digoxin is used in the treatment of cardiac failure, atrial fibrillation and flutter, paroxysinal tachycardia, cardiac insufficiency, etc. It has the advantage as compared to digitoxin, in that its onset of action is quite more rapid and further, its duration of action is shorter. It has an additional advantage in that in the event of an overdose, the symptoms associated therewith are more readily dissipated; however, digoxin is not as completely absorbed from the gastrointestinal tract as digitoxin. Essentially, digoxin is absorbed only to the extent of about 50% to 70%. Its solubility per ml of 0.1 N HCl is about 78 mcg. at 25.degree. C.
The low solubility of digoxin in water and in other various media such as artificial gastric juice (e.g. 0.1 N HCl) has heretofore restricted its medicinal value. On the other hand, the therapeutic and toxic dose of digoxin are extremely close. Consequently, the difference in the absorption of digoxin observed (due to its low solubility) and its varying rate of absorption in different individuals, can cause toxic effects.
To date, numerous efforts have been directed to obtaining a derivative of digoxin exhibiting favorable physical properties, which would permit such derivatives to be administered for the purpose of enabling digoxin to be released in the bloodstream at a high bioavailable level, without exhibiting accompanying toxic side effects. A review of the literature respective of these derivatives follows: EQU OH.sub.4.sub.'.sub." .perspectiveto. OH.sub.3.sub.'.sub." &gt; OH.sub.12 .apprxeq. OH.sub.3.sub." &gt; OH.sub.3.sub.'
On the other hand, the digoxin molecule contains a base-sensitive lactone ring, which in basic solution or solutions, will undergo irreversible rearrangement. Strong acids, however, split off the digitoxose moieties.
Thus, the most reactive part of the molecule is the 3'" and 4'" hydroxy groups. A number of derivatives have been prepared by reacting the hydroxy groups in digoxin as outlined below.
U.S. Pat. No. 3,538,078, Belgian Pat. No. 752,284 and German Pat. No. 1,961,034 have disclosed digoxin ether derivatives of the 3'", 4'"-mono-ether type, the di-ethers, and the mono-ethers-monoacylates. Specifically, the 3'"-monoethyl ether, the 3'"-monomethyl ether, the dimethyl ether, the monoacetyl-monoethyl ether, the monoformyl-monomethyl ether, the monoethoxyacetyl-monomethyl ether, the 4'"-monomethyl ether, and the 4'"-monoethyl ether have been disclosed.
Belgian Pat. No. 672,307 discloses digoxin acylates, such as the tetraformate (4'", 3'", 3" and 3').
Belgian Pat. No. 750,875 and German Pat. No. 2,019,967 disclose digoxin derivatives of the pentanitrate and mono-di and -tetranitrate type.
Belgian Pat. No. 763,817 discloses digoxin derivatives of the 3'" and 4'"-monoacylate type, employing an alkyl-ortho-acetate. The same compounds are disclosed as being derived from the separation of same out of a mixture of glucosides in French Pat. No. 1,568,075.
Other 3'"-monoacylates of the formula: ##STR4## are known wherein R' represents a substituted alkyl group of from one to four carbon atoms, whose substituents are either a halogen atom, an aryl group (preferably, a phenyl group) or a cycloalkyl group; a straight alkyl group of from 2 to 12 carbon atoms, or a cycloalkyl group of from three to eight carbon atoms. See, German Pat. No. 2,101,595.
U.S. Pat. No. 3,514,441 discloses 12-monoacylates of digoxin obtained by protecting the 3'" and 4'" hydroxy groups by forming a 3'" or 4'"-carbonate or a 3'", 4'"-cyclocarbonate. The aforementioned protecting groups can easily be removed, selectively, following acylation of the C.sub.12 hydroxy group.
A number of digoxin derivatives have been prepared in the prior art by effecting structural changes of the steroid part, such as the digoxin 15', 16'-diacetates. For instance, see Belgian Pat. No. 749,680.
Belgian Pat. No. 751,768 discloses the 22-n-butoxy; the 22-fluoro; and the 22-methoxy forms of digoxin.
German Pat. No. 2,052,634 discloses derivatives substituted on the lactone ring of digoxin by a group of the --HC=C(R.sub.1,R.sub.2) type, wherein R.sub.1 represents a CN group, a COOH group, and a carboalkoxy group, and wherein R.sub.2 represents a hydrogen atom, a flourine atom, a chlorine atom, an alkyl group, an alkoxy group, or a CN group.
Dutch Pat. No. 66-01041 discloses 12-dehydro digitoxin and Swiss Pat. No. 413,812 discloses dihydrodigoxin.
Finally, U.S. Pat.No. 3,696,091 discloses 22-substituted (F, Cl, alkoxy) digoxin ether and acylates.
Since the inventor's main objective concerned the development of transient digoxin derivatives having higher water solubility and absorption characteristics (higher bioavailability levels), he was extremely interested in only the activity and physical properties of the simple reported digoxin derivatives, i.e., the ethers and acylates.
While all reported derivatives thus prepared in the prior art are claimed to exhibit superior therapeutic and/or physicochemical properties than digoxin per se, this is not exactly true. For instance, it is still questionable whether digoxin ethers are hydrolyzed enzymatically. Recent reports seem to indicate that 4'"-methyldigoxin is actually demethylated in man. In this regard, reference is made to the articles by H. Rennekamp, C. H. Rennekamp, U. Abshagen, K. V. Bergmann, and N. Rietbrock, Arch. Pharmacol, 273, 172 (1972) and N. Reitbrock, C. H. Rennekamp, H. Rennekamp, K. V. Bergmann and U. Abshagen ibid, 272, 450 (1972) respectively.
However, more recent studies conclude that "beta-methyldigoxin is very resistant to degradation by animal enzymes. Methyl digoxin is a new glycoside, but not a form of digoxin which exhibits improved absorption, i.e., bioavailability. The metabolism of digoxin appears to be inhibited by substituting the beta-hydroxy group of the third digitoxose molecule." On the other hand, it is generally accepted that acetyl digoxin is rapidly hydrolyzed giving rise to digoxin. See, G. Haberland, Arzneimittel Forsch, 15, 481 (1965); K. Buchtela, U. Drexler, H. Hackl, N. Konigstein, and O. Schlager, ibid, 18, 295 (1968); and W. Forster and S. Schulzeck, Biochem. Pharmacol., 17, 489 (1968).
U.S. Pat. No. 3,884,905, in the name of the present inventor, discloses the mono- through penta- nocotinate, isonicotinate and picolinate derivatives of digoxin.